The Power of the Mighty Mouse: A Conversation with Jeffrey Mogil

This is the fourth in a series of Forum interviews with PRF science advisors. 

 

Jeffrey Mogil, PhD, is the E. P. Taylor Professor of Pain Studies and the Canada Research Chair in the Genetics of Pain in the Department of Psychology at McGill University in Montreal. He helped found the field of pain genetics, starting with his seminal studies on differences in pain sensitivity and susceptibility across common laboratory mouse strains. Mogil also studies sex differences in pain and analgesia, and developed the “grimace scale,” a method for quantifying pain in mice based on the animals’ facial expressions. He also serves as a section editor for the journal Pain. Megan Talkington spoke with Mogil by phone for an update on his work, his views on pain research, and his hopes for the field. The following is an edited transcript of their conversation.

 

What in your research are you most excited about right now?

 

We are branching out a lot these days. I've made my career largely on the back of genetics, and quite randomly we started finding sex-specific genetic interactions, which got me very interested in sex differences in pain. This is still a really interesting story. I'm having the most fun with the work we’ve been doing on social modulation, and we’re onto a pretty interesting story right now regarding cross-species social modulation of pain. We are making up new contraptions and devices in experimental paradigms to test these theories, working without a map at all, which I like.

 

I still like genetics, but genetics became too simple. It's very brute force now: You collect some data, run them through the databases, the genes show up, and all you really need to do is separate the true positives from the false positives. It's very important, but I'm actually really enjoying the psychology experiments. I am, after all, a professor of psychology. I was always a bit of a fish out of water—a pain researcher in a psych department.

 

Can you say more about the social modulation work?

 

We are finding astoundingly robust effects on pain in mice depending on what other mice are around and what their relationship is to each other. It's really interesting because it depends on many factors we can track down, and it involves pheromones.

 

It started with our empathy paper [which reported that mice’s pain sensitivity was modulated by the pain state of their cage mates; see Langford et al., 2006], but we've done a bunch of follow-ups. The social environment is thought to be important in humans, but nobody really expected one could study this in animals at all. People talk about the biopsychosocial model, and everyone's idea is that mice and rats are for the bio part and the psychosocial part can only be done in humans. I don’t think this is true, and hopefully we are starting to show that. It’s exciting to do psychosocial pain modulation experiments in mice where, once you figure out the phenomena, you can start using all the power of genetics and pharmacology to flesh out the mechanisms. Human psychosocial modulation of pain almost certainly is built on the same principles.

 

In addition, I've been very impressed with the utility of pain as a way to study social neuroscience. That is to say, when people study social interactions in mice and rats, they usually put the animals together and see how much time they spend with each other. But, we've found that if you put two mice together in social situations, and one or both of them are in pain, it actually changes the social situation in a way that is particularly interesting to study. This might have relevance to conditions like autism. It’s pain as a means to another end, not an end in and of itself. Of course, this has never really been done at all—people have done experiments with shock, but not with tonic or chronic pain.

 

What else is going on in your lab?

 

A unit was created for us in our lab that we think will help us test mice for a pretty advanced psychological concept called somatization, or somatic awareness, which is thought to be relevant to pain. I have become very interested in somatic awareness because the OPPERA study [Orofacial Pain: Prospective Evaluation and Risk Assessment; see PRF related news story] found that this is the number one predictor of who develops chronic TMD [temporomandibular disorders]. Every so often, people get tingles and weird feelings in their bodies, and while most people notice it, they then forget about it. But some people don't forget about it at all and tend to perseverate on those sorts of sensations. Those people are at the highest risk to develop chronic pain, or at least TMD.

 

We’ve actually figured out how to test that same thing in a mouse. We are going to implant a sterile magnet in the body, mid-scapula. We just had a device made that's going to impose a magnetic field that can be slowly increased. It’s going to start vibrating the magnet, and at some point, the mice are going to notice that—it's not going to be painful, but they will feel something moving around, and we expect they will start scratching at it to figure out what's going on. We're hoping and expecting that we’ll see variability in both the amount of scratching they do when the magnet is on, and even better if there is scratching (or some other behavior) that continues after the magnetic field is turned off. That, in our minds, would represent somatization. We call it the "Princess and the Pea test."

         

Once we can show that, we can then start doing genetic and pharmacology experiments to see if, in fact, this predicts who is more susceptible to developing chronic pain symptoms. Somatization is a perfect example of something you would expect to be farcical to study in animals, but I really believe it's possible. To see what I can study in a mouse that everyone thinks can't possibly be studied—if there is any sort of guiding ambition I have at the moment, that's it.

 

I’m also wondering whether, over the course of your career, you’ve found anything that really surprised you.

 

I'm still surprised at the extent of sex differences in pain—just how different the circuitry really seems to be. What's in the literature right now is the tip of the iceberg, and people are really going to be surprised, in the fullness of time, to see just how different the neural circuits are in males and females.

 

I'm also surprised, and dismayed, at how complicated everything in biology is. The more you learn, the more you realize that the system is far more complicated than you thought it was, so you are actually moving further away from the goal instead of closer to it.

 

I’m also surprised at how nice everyone in the pain field is. In fact, a case can be made that they are too nice—that everyone is too polite and there is very little fighting and arguing, at least publicly. I have heard and continue to hear stories of colleagues in other fields backbiting and yelling at each other in meetings—really angry and aggressive stuff. I don't see any of that in the pain field.

 

Does the pain field need, maybe not more aggression, but more debate?

 

More spirited debate at meetings would actually help the field. Part of the issue is that there aren't any big debates left in pain. Pattern versus specificity always simmers in the background, but it's not like it is in other fields, where there are two or three dominant theories and all the data fit one theory or the other—so at the end of their talks, people say, “Here are my data and, as you notice, they support theory A of memory,” and then everyone who’s invested in theory B starts arguing.

 

We really don't have that in the pain field. There is only one dominant theory—sensitization—so there is nothing to argue about. People show their data and say, “We’ve implicated this new molecule in pain,” and the experiments are all the same as everyone else's experiments. People clap politely and say, “Yes, you've definitely shown that molecule is involved in pain.” But then the next speaker, using the same type of experiments, tells you about a completely different molecule that he or she has implicated in pain. There's nothing wrong with that—we need to know the molecules. It's just that there is no debate that can be had.

 

We need new theories. If our current theories were all-powerful, then we probably would have seen better translation into the clinic. But you can't wish theories into existence. Someone is going to have to come up with something that actually argues against the current dominant theory, and no one has come up with that yet.

 

Is there a big question in pain that the field needs to address, but isn’t?

 

Yes, but this is not going to surprise anyone, since I've been writing and talking about this at meetings for years. The elephant in the room is that no one studies spontaneous chronic pain. Everyone studies mechanical allodynia, but mechanical allodynia is nowhere near as important a symptom as spontaneous chronic pain. So the most important symptom in clinical pain is more or less being ignored by the vast majority of the preclinical community, simply because we don't know how to measure it, or can't agree on how to measure it, or think that measuring it is too difficult.

 

Do you see any progress being made on that count?

 

Absolutely. Finally, people are coming up with potential new measures to assess pain. My lab came up with mouse facial expression, and that is helpful in certain circumstances. Conditioned place preference has been rediscovered, and that seems to be working well for some people. People are primed now, if not to throw down their von Frey fibers forever, then to at least supplement them with other measures, which reviewers are starting to demand.

 

What other questions deserve more attention?

 

There is too much focus on the dorsal root ganglion and the spinal cord. The imagers are working at supra-spinal sites, but they are limited in what they can do: They can reveal the anatomy, but at the end of the day, drug development is driven by neurochemistry, not anatomy. It almost doesn't matter where precisely the drugs work—it matters entirely what their molecular targets are, and you don't learn that from imaging. Preclinical research has to move up the neuraxis. We have been resisting that because it has been much more complicated, but ultimately we have to go there.

 

One question that's never been answered satisfactorily in my mind, and that bears upon how much of a priority it is to get above the spinal cord, is just what the effect of lidocaine blocks are on pain. To the extent that lidocaine blocks make pain go away in chronic pain patients, at least acutely, that means you should be studying the periphery. To the extent that they don't work means that the pain generator isn't in the periphery anymore—it's central now—and studying the periphery isn't going to help. The question is: How often, and in what conditions, do lidocaine blocks work? We only have partial answers to that question. Sometimes when the block doesn't work or doesn't get rid of all the pain, the convenient excuse is the lidocaine didn't get in. Clinical scientists can do basic scientists a real favor by going back to really answer that question systematically. That would help us basic scientists know whether we should continue our careers out in the periphery or move up in the neuraxis.

 

Are there any other places where the field is getting stuck?

 

The field isn't as diverse as it ought to be in terms of people’s backgrounds. There are a lot of electrophysiologists studying pain because that's where the field came from, and there are a lot of anatomists. But there are disciplines that are perfectly relevant to pain research, but where no one is doing it—and they should.

 

The example I have been thinking about is ethology [the science of animal behavior]. Ethologists have developed pseudo-natural environments in the lab where mice live in colonies as they normally do. It would be fascinating to see what mice with chronic neuropathic pain do—how they live—in a more natural environment. I've tried to do that, but I don't know a thing about ethology. If people who were actually trained in that area came into the pain field, they would probably notice things that the rest of us are missing.

 

Are there other disciplines you have in mind?

 

They all come from the squishier end of the spectrum. For example, there is room for many more card-carrying social psychologists in the pain field.

 

Also, there is a completely artificial split among people who go to meetings with the word “pain” in the title (essentially the anesthesiologists) and the headache people (the neurologists) who go to completely different meetings, and then the arthritis people (the rheumatologists), who also go to completely different meetings. It would be tremendous if we could all meet under the same tent. I've never been convinced that there is anything fundamentally different about pain in different parts of the body just because, historically, they have been studied by different medical specialties. We are really all studying the same thing, and we should admit it.

 

If scientists and stakeholders started thinking of pain as a single entity that comes in different flavors, then the public would recognize the true scope of pain as a health problem. The public doesn't realize that chronic pain is the most prevalent human health problem, by far, because pain has been divided into separate, arbitrary categories. If you simply lump back pain, headache, and arthritis together, suddenly you are talking about something that half the population has, which just swamps out the prevalence of everything else. But of course, people don't lump those together; they think of them as completely different diseases. This is hurting us in terms of funding. Other diseases have bike-a-thons: Where's the bike-a-thon for pain? Money that comes in from the organizations running such events is really useful for funding research. Cancer researchers can send in their grants to the NIH, but they can also be funded by many different private foundations. Pain researchers in the U.S. basically have one funding source: the NIH. That's all there is.

 

What's your dream project? If you were given the resources to do any project you’d like, what would it be?

 

I'm going to evade that question to make a point. I'm not a big proponent of big science. Putting that many of your funding eggs in a single dream experiment basket is almost always a bad idea; it's never cost-effective. I refuse to even play along by coming up with a single experiment I would do if someone gave me $20 million. That sum should not be spent on a single experiment; it should be spread far and wide. The result of that investment is going to be more, on average, than trying to pick a winner and giving the winner ridiculous amounts of money. The problem with that idea is that a lot of people love big science, especially bureaucrats and politicians, who want to be able to claim that they funded an incredibly important mega-study. This is instead of supporting the much less sexy idea of putting as much money as your society can afford into a pool and hoping and expecting that someone, somewhere, is going to get lucky, or be brilliant, or some combination of the two, and come up with something interesting and useful.

 

As my career has gone forward, in fact, I've been quite consciously trying to make my studies cheaper. In fact, we did a little back-of-the-napkin calculation on what it cost to do the studies in the empathy paper in 2006. If you actually looked at what it cost to keep the mice alive, and buy whatever reagents were needed, the study cost less than $10,000. A study that gets into Science that costs less than $10,000—this is almost never done anymore. I'm not trying to blow my own horn that I'm such a cost-effective scientist. I'm just saying that we would be far better off as a society if we resisted the desire of politicians to have big-ticket biology studies. The history of science has proven that is not a good idea.

 

Is there a particular paper or book that you think every pain researcher should read?

 

The answer may sound a little bit self serving, but I’m going to recommend an analysis of the field that I published in Pain a few years ago [Mogil et al., 2009]. In that paper are two really interesting top-25 lists. One is of the papers published in Pain that have received the most citations. Another one—this is even more interesting—is of the papers and books that have been published somewhere other than Pain, but that have received the most citations in papers actually published in Pain.

 

If you want to be well rounded in the field, having at least some familiarity with the papers on those two lists would serve you well. It's really interesting to notice what the papers are. Most of them, obviously, describe techniques, but some of them report actual findings, and to get a sense of which findings have garnered the most interest over the years is pretty interesting.

 

Is there a question you wish I had asked you but didn't?

 

You didn't ask me how I came to be here!

 

Can you tell me about that?

 

I'm here completely by accident. I thought I was going to go to med school, and probably would have, except I caught the science bug in my fourth year of undergraduate work, when I took a lab course in what would now be called behavioral neuroscience. We did some rat experiments—which is almost impossible now, because it's so complex to get ethical approval for students to do experiments on rats, which really is too bad, because that was the thing that got me interested enough to join the field. Anyway, I ended up being a lab technician for a year for a guy who worked on reward systems.

 

When I applied to graduate school, everyone I applied to work with was a reward person, except, somehow, John Liebeskind [at the University of California, Los Angeles, US]. To be honest, I don't know how he got on the list, since he wasn't in the right field. It wasn't that his science impressed me more than anyone else’s; it was that he impressed me personally. So the next thing I knew, I was a pain researcher. I justified it at the time by saying, “Pleasure, pain—flip sides of the same coin.” So it was completely arbitrary that I became a pain researcher and that I started doing genetics.

 

How did you move into genetics?

 

The first year I was in graduate school, Marshall Devor [at the Hebrew University of Jerusalem in Israel] published a paper where he had selectively bred rats for high and low autotomy after denervation, and he did an analysis suggesting that a single gene was responsible for the difference (Devor and Raber, 1990). A postdoc in our lab had helped develop, in Poland, mice that were selectively bred for high and low analgesia. We read this paper and thought we could do exactly the same experiment that Marshall did in rats. So I started doing pain genetics, and for a long time, no one cared. I used to go to meetings, and people would come by my poster and politely let me walk them through it. But it became clear that they were really there just so they could tell me to say hi to John Liebeskind for them.

 

Then, suddenly, the knockout technique was developed, and geneticists from other fields started pointing out that the phenotypes of knockout mice depended on the background strains. Then people started to ask what we knew about the background strains and their pain sensitivity. It just turned out that I was the only one who ever collected such data. Suddenly, what was uninteresting to people became interesting, not because of anything I did, but because of some random change in the world that happened to come along at the same time, and I was simply the beneficiary of that.

 

Thanks so much for speaking to PRF.

 

Thank you.

 

 

CORRECTION (28 May 2012). In the original version of this Forum, John Liebeskind’s last name was misspelled. In addition, the sentence “If you simply lump pain, headache, and arthritis back together…” should have read “If you simply lump back pain, headache, and arthritis together....” The text in both cases has been corrected.

 

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PRF Related Content:

News: P2X7 Receptor Gene Variants Modulate Chronic Pain (1 Apr 2012)

 

News: Progress in Pain Genetics: A Meeting of Their Own (14 Mar 2012)

 

News: Sex and Drugs and Stress and Genetic Variation: Very Complicated Indeed (28 Oct 2011)

 

News: Power in Numbers (6 Jun 2011)

 

Forum Discussion: What Is the Reason for Lack of Translation in the Pain Field? (28 Mar 2011)

 

View Jeffrey Mogil's profile on Pain Research Forum (requires member log in)

 

Additional Reading:

Mogil JS. Pain genetics: past, present and future. Trends Genet. 2012 Mar 28. [Epub ahead of print]

 

Mogil JS, Bailey AL. Sex and gender differences in pain and analgesia. Prog Brain Res. 2010; 186:141-57.




Mogil JS, Davis KD, Derbyshire SW. The necessity of animal models in pain research. 
Pain. 2010 Oct; 151(1):12-7. 

 

Langford DJ, Bailey AL, Chanda M L, Clarke SE, Drummond TE, Echols S, Glick S, Ingrao J, Klassen-Ross T, Lacroix-Fralish ML, Matsumiya L, Sorge RE, Sotocinal SG, Tabaka JM, Wong D, van den Maagdenberg AMJM, Ferrari MD, Craig KD, Mogil JS. Coding of facial expressions of pain in the laboratory mouse. Nat Methods. 2010 Jun; 7(6):447-9. 

 

Mogil JS, Simmonds K, Simmonds MJ. Pain research from 1975 to 2007: a categorical and bibliometric meta-trend analysis of every Research Paper published in the journal, Pain. Pain. 2009 Mar; 142(1-2):48-58. 

 

Langford DJ, Crager SE, Shehzad Z, Smith SB, Sotocinal SG, Levenstadt JS, Chanda M L, Levitin DJ, Mogil JS. Social modulation of pain as evidence for empathy in mice. Science. 2006 Jun 30; 312(5782):1967-70.

 

Other Resources:

The Mogil Laboratory page 

Pain Genes Database

 

Other Forum Interviews:

Easing Pain the World Over: A Conversation with Kathleen Foley (4 May 2012)

 

Revealing the Inner Workings of Pain: A Conversation with Clifford Woolf (11 May 2012)

 

Moving Safer, More Effective Pain Medicines to Market: A Conversation with William Schmidt (18 May 2012)

 

Promoting a Culture of Evidence: A Conversation with Christopher Eccleston (1 June 2012)

 

Pain and Its Control: A Conversation with Allan Basbaum (6 June 2012)

 

The Power of the Collective: A Conversation with Stephen McMahon (29 June 2012)

 

Contrarian Thinking in Pain Research: A Conversation with Marshall Devor (6 July 2012)